ISG15 deficiency and increased viral resistance in humans but not mice

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ISG15 is an interferon (IFN)-α/β-induced ubiquitin-like protein. It exists as a free molecule, intracellularly and extracellularly, and conjugated to target proteins. Studies in mice have demonstrated a role for Isg15 in antiviral immunity. By contrast, human ISG15 was shown to have critical immune functions, but not in antiviral immunity. Namely, free extracellular ISG15 is crucial in IFN-I 3-dependent antimycobacterial immunity, while free intracellular ISG15 is crucial for USP18-mediated downregulation of IFN-α/β signalling. Here we describe ISG15-deficient patients who display no enhanced susceptibility to viruses in vivo, in stark contrast to Isg15-deficient mice. Furthermore, fibroblasts derived from ISG15-deficient patients display enhanced antiviral protection, and expression of ISG15 attenuates viral resistance to WT control levels. The species-specific gain-of-function in antiviral immunity observed in ISG15 deficiency is explained by the requirement of ISG15 to sustain USP18 levels in humans, a mechanism not operating in mice.

Original languageEnglish (US)
Article number11496
JournalNature Communications
StatePublished - May 19 2016
Externally publishedYes


ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

Cite this

Speer, S. D., Li, Z., Buta, S., Payelle-Brogard, B., Qian, L., Vigant, F., Rubino, E., Gardner, T. J., Wedeking, T., Hermann, M., Duehr, J., Sanal, O., Tezcan, I., Mansouri, N., Tabarsi, P., Mansouri, D., Francois-Newton, V., Daussy, C. F., Rodriguez, M. R., ... Bogunovic, D. (2016). ISG15 deficiency and increased viral resistance in humans but not mice. Nature Communications, 7, [11496].